US11096906B2 - Pharmaceutical composition for preventing or treating Alzheimer's disease - Google Patents

Pharmaceutical composition for preventing or treating Alzheimer's disease Download PDF

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US11096906B2
US11096906B2 US15/777,529 US201615777529A US11096906B2 US 11096906 B2 US11096906 B2 US 11096906B2 US 201615777529 A US201615777529 A US 201615777529A US 11096906 B2 US11096906 B2 US 11096906B2
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pharmaceutical composition
treating alzheimer
disease
disease according
methylphloroglucinol
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So-young PARK
Hwan-Bin JOO
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Sfcbio Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/11—Pteridophyta or Filicophyta (ferns)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/11—Pteridophyta or Filicophyta (ferns)
    • A61K36/12—Filicopsida or Pteridopsida
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present disclosure relates to a use of a phloroglucinol-based compound and its salt for preventing and treating Alzheimer's disease.
  • Dementia is a pathological condition which should be distinguished from normal aging. It is divided into Alzheimer's disease, vascular dementia and other dementias caused by alcoholism, trauma and sequela of Parkinson's disease according to the cause. Among them, Alzheimer's disease is known to be caused primarily by the toxicity of the neurotoxic protein ⁇ -amyloid.
  • ⁇ -amyloid is produced gradually from the amyloid precursor protein (APP) via the amyloidogenic pathway.
  • APP amyloid precursor protein
  • the produced monomeric ⁇ -amyloid is aggregated with each other to form an oligomer.
  • the aggregated form of ⁇ -amyloid induces neuronal cell death.
  • acetylcholine precursors or drugs inhibiting the degradation of acetylcholine are administered as dementia medications in order to increase the concentration of acetylcholine in the brain.
  • Representative drugs include tacrine, donepezil, rivastigmine, galantamine, etc.
  • the existing dementia medications mainly inhibit the acetylcholinesterase without preventing the formation or aggregation of ⁇ -amyloid, they cannot ultimately prevent or cure dementia.
  • the existing dementia medications are cholinergic drugs, they have the problems that they cannot be administered in combination with other cholinergic drugs, they may inhibit the effect of anticholinergic drugs, they may stimulate the vagus nerve by acting on the cardiovascular system and care should be taken when they are used in patients with a history of severe asthma or obstructive pulmonary disease.
  • the inventors of the present disclosure have studied Dryopteris crassirhizoma for treatment and prevention of Alzheimer's disease. In doing so, they have found a use of an active ingredient capable of suppressing the production of ⁇ -amyloid from the ingredients of the herb, which has never been mentioned or studied regarding Alzheimer's disease, and have completed the present disclosure.
  • the present disclosure is directed to providing a pharmaceutical composition for preventing or treating Alzheimer's disease.
  • the present disclosure is also directed to providing a method for preparing a pharmaceutical composition for preventing or treating Alzheimer's disease, which includes extracting and separating an active ingredient from Dryopteris crassirhizoma and formulating the same.
  • the present disclosure provides a pharmaceutical composition for preventing or treating Alzheimer's disease, which contains a phloroglucinol-based compound, an isomer thereof or a salt thereof.
  • the present disclosure also provides a method for preparing a pharmaceutical composition for preventing or treating Alzheimer's disease, which includes extracting and separating an active ingredient from Dryopteris crassirhizoma and formulating the same.
  • a pharmaceutical composition for preventing or treating Alzheimer's disease of the present disclosure fundamentally suppresses the cause of ⁇ -amyloid formation, thereby exerting a remarkable effect of allowing ultimate treatment of Alzheimer's disease.
  • the present disclosure provides a use of a single substance, which has been isolated from Dryopteris crassirhizoma and identified, for preventing or treating Alzheimer's disease for the first time.
  • FIG. 1 shows an exemplary extraction process for obtaining a compound according to the present disclosure.
  • FIG. 2 shows an exemplary process of obtaining fractions for obtaining a compound according to the present disclosure.
  • FIG. 3 shows the 1 H-NMR spectrum of Compound 1 identified as a single substance.
  • FIG. 4 shows the 13 C-NMR spectrum of Compound 1 identified as a single substance.
  • FIG. 5 shows the structure of Compound 1.
  • FIG. 6 shows the 1 H-NMR spectrum of Compound 2 identified as a single substance.
  • FIG. 7 shows the 13 C-NMR spectrum of Compound 2 identified as a single substance.
  • FIG. 8 shows the structure of Compound 2.
  • FIG. 9 shows the 1 H-NMR spectrum of Compound 3 according to the present disclosure.
  • FIG. 10 shows the 13 C-NMR spectrum of Compound 3 according to the present disclosure.
  • FIG. 11 shows the structure of Compound 3 according to the present disclosure.
  • FIG. 12 shows a result of investigating the cytotoxicity of Compounds 1 and 2.
  • FIG. 13 shows a result of investigating the cytotoxicity of Compound 3.
  • FIG. 14 shows a result of investigating the inhibition of ⁇ -amyloid formation by Compounds 1-3 through western blot.
  • FIG. 15 shows a result of comparing the inhibition of ⁇ -amyloid formation by Compounds 1-3.
  • FIG. 16 shows a result of investigating the effect of Compound 1 on ⁇ -secretase through western blot.
  • FIG. 17 shows a result of investigating the effect of Compound 1 on ⁇ -secretase.
  • FIG. 18 shows a result of investigating the effect of Compound 2 on ⁇ -secretase through western blot.
  • FIG. 19 shows a result of investigating the effect of Compound 2 on ⁇ -secretase.
  • FIG. 20 shows a result of investigating the effect of Compound 3 on ⁇ -secretase through western blot.
  • FIG. 21 shows a result of investigating the effect of Compound 3 on ⁇ -secretase.
  • the present disclosure relates to a pharmaceutical composition for preventing or treating Alzheimer's disease, which contains a phloroglucinol-based compound, an isomer thereof or a salt thereof.
  • the phloroglucinol-based compound defined in the present disclosure has a basic structure of Chemical Formula 1:
  • positions 2 and 4 may be substituted with an alkyl or acyl group.
  • the phloroglucinol-based compound of the present disclosure may be one or more selected from a group consisting of butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol and 2-butyryl-4-methylphloroglucinol.
  • butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol and 2-butyryl-4-methylphloroglucinol exert a remarkable effect of inhibiting ⁇ -amyloid formation without showing cytotoxicity at an effective concentration (see FIGS. 12-21 ).
  • Compound 3 which showed toxicity at a concentration of 100 ⁇ g/mL, reduced the amount of sAPP ⁇ almost perfectly at 20 ⁇ g/mL where no toxicity was observed and also effectively decreased the amount of ⁇ -secretase in Test Example 1.
  • an increased administration dose of an active ingredient, etc. generally leads to increased cytotoxicity and drug-related side effects
  • the remarkable effect at a low administration dose means a high value as a drug for treating Alzheimer's disease.
  • the pharmaceutical composition of the present disclosure may contain one or more active ingredient selected from a group consisting of butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol, 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof.
  • the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains one of butyryiphloroglucinol, 2-propionyl-4-methylphloroglucinol, 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
  • the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains butyryiphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
  • the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains 2-propionyl-4-methylphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
  • the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
  • the salt contained in the pharmaceutical composition of the present disclosure may be a physiologically acceptable salt of an inorganic acid, an organic acid, an inorganic base or an organic base.
  • the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid
  • the organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc., although not being limited thereto.
  • Alzheimer's disease used in the present disclosure refers to dementia caused by Alzheimer's disease, i.e., dementia caused by formation and buildup of ⁇ -amyloid in the brain tissue. Any dementia caused by formation and buildup of ⁇ -amyloid is included in the scope of the present disclosure.
  • the pharmaceutical composition for preventing or treating Alzheimer's disease containing the phloroglucinol-based compound according to the present disclosure may be applied to an animal including human.
  • the phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure may be prepared through chemical synthesis or may be obtained by extracting from Dryopteris crassirhizoma.
  • the phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure is isolated from Dryopteris crassirhizoma.
  • Dryopteris crassirhizoma is a perennial grass belonging to the family Dryopteridaceae (Aspidiaceae).
  • the phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure may be obtained by cold extraction, hot extraction, thermal extraction, ultrasonic extraction, etc. using a commonly used extractor, ultrasonic extractor or fractionator.
  • the phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure may be isolated by extracting with one or more solvent selected from a group consisting of propanol, isopropanol and methanol. Specifically, one or more solvent selected from a group consisting of isopropanol or butanol may be used.
  • the solvent used in the extraction may be diluted to 50-99% (v/v) with water.
  • the filtrate may be concentrated using a vacuum rotary evaporator or a vacuum drier and then stored at room temperature.
  • the extract may be further fractionated simultaneously or sequentially using one or more solvent selected from a group consisting of hexane, methylene chloride, ethyl acetate, butanol and water.
  • the fractionation solvent may be specifically butanol, more specifically 30-99% (v/v) butanol diluted with water.
  • the fraction may be concentrated using a vacuum rotary evaporator or a vacuum drier and then stored at room temperature.
  • the fraction obtained by fractionating simultaneously or sequentially using one or more solvent selected from a group consisting of hexane, methylene chloride, ethyl acetate, butanol and water may be separated by ion-exchange chromatography, silica gel chromatography or medium pressure liquid chromatography (MPLC).
  • a solvent used in the chromatography specifically methanol, acetonitrile or methyl chloride may be used, although not being limited thereto.
  • the phloroglucinol-based compound according to the present disclosure provides a remarkable use in preventing or treating Alzheimer's disease.
  • the phloroglucinol-based compound can fundamentally suppress the formation of ⁇ -amyloid by reducing sAPP ⁇ in a concentration-dependent manner (see FIGS. 14 and 15 ).
  • the phloroglucinol-based compound can fundamentally suppress the formation of ⁇ -amyloid by inhibiting ⁇ -secretase in a concentration-dependent manner (see FIGS. 16-21 ).
  • the pharmaceutical composition containing the phloroglucinol-based compound of the present disclosure, an isomer thereof or a salt thereof can suppress the formation of ⁇ -amyloid, which is the fundamental problem of Alzheimer's disease, unlike the currently commercially available drugs that simply suppress the progress of Alzheimer's disease through metabolism of acetylcholine, such as tacrine, donepezil, rivastigmine, galantamine, etc. Accordingly, the pharmaceutical composition of the present disclosure can be used directly for preventing and treating Alzheimer's disease.
  • the administration dose of the pharmaceutical composition according to the present disclosure may be determined by considering administration method, the age, sex and condition of a patient, the severity of a disease, the absorption rate of the active ingredient in vivo, the rate of inactivation and the drug administered in combination.
  • the daily dosage of the active ingredient may be 0.1-500 mg/kg (body weight), specifically 0.1-400 mg/kg (body weight), more specifically 1-300 mg/kg (body weight) and the administration may be made once or several times a day, although not being limited thereto.
  • composition according to the present disclosure may be formulated by containing an inert carrier, a diluent or both of them.
  • inert carrier or diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, corn starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, citric acid, tartaric acid, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, physiological saline, etc., although not being limited thereto.
  • the pharmaceutical composition of the present disclosure may further contain a commonly used filler, extender, binder, disintegrant, anti-agglomerant, lubricant, wetting agent, pH control agent, nutrient, vitamin, electrolyte, alginic acid or its salt, pectic acid or its salt, protective colloid, glycerin, fragrance, emulsifier, antiseptic, etc.
  • the pharmaceutical composition according to the present disclosure may be prepared into an oral or parenteral formulation by containing an additive including the above-described carrier or diluent.
  • Formulations for oral administration include a tablet, a capsule, a pill, a powder, a granule, a suspension, a syrup, etc.
  • Formulations for parenteral administration include a cream, a lotion, an ointment, a liquid, a gel, a cataplasma, a patch, an aerosol, a fluid extract, an elixir, an infusion, a sachet, an injection, etc.
  • the content of the phloroglucinol-based compound in the pharmaceutical composition for preventing or treating Alzheimer's disease may be 0.001-99.9 wt %, 0.1-99 wt % or 1-50 wt %. However, the content may be controlled adequately without being limited thereto.
  • the pharmaceutical composition for preventing or treating Alzheimer's disease of the present disclosure may further contain a substance known to be effective in treating dementia in addition to the active ingredient.
  • a substance known to be effective in treating dementia may include tacrine, donepezil, rivastigmine, galantamine, etc., although not being limited thereto.
  • the concentrated methanol or isopropanol extract of Dryopteris crassirhizoma was fractionated with two immiscible solvents based on the difference in polarity. Hexane, methylene chloride, ethyl acetate, butanol and water layers were fractionated and concentrated sequentially. This process was repeated 3 times. The concentrates were stored at 4° C. until use. 16 g of a hexane layer, 3 g of a methylene chloride layer, 54 g of an ethyl acetate layer, 80 g of a butanol layer and 140 g of a water layer were obtained.
  • the fractionated butanol layer extract (80 g) was subjected to MCI column chromatography. 30-100% methanol was used as a mobile phase and a total of 6 fractions were obtained (S1-S6). Based on TLC and HPLC results, the fifth fraction (S5, 3.5 g) was separated by MPLC.
  • Compound 1 (10 mg), Compound 2 (5.5 mg) and Compound 3 (15 mg) were obtained as pure single substances from the 1st fraction (255 mg) through HPLC (solvent: 40-50% ACN).
  • Compound 3 was separated as a scarlet powder.
  • Test Example 1 Investigation of Toxicity of Identified Compounds
  • cytotoxicity of Compounds 1-3 separated and identified in Examples 1-5 was investigated by MTT-based cytotoxicity assay.
  • APP*t-CHO cells treated with Compounds 1-3 were cultured for 24 hours. After adding a 5 mg/mL MTT solution, the cells were cultured for 4 hours. After removing the culture medium and lysing the cells for 30 minutes by adding DMSO, absorbance was measured at 540 nm using the Emax precision microplate reader (Molecular Devices, CA, USA).
  • Compounds 1 and 2 showed no toxicity even at the concentration of 100 ⁇ g/mL, whereas Compound 3 showed toxicity at the concentration of 30 ⁇ g/mL or higher (see FIGS. 12 and 13 ).
  • APP wt -CHO cells obtained by overexpressing APP in CHO cells were used and the amount of the sAPP ⁇ protein cleaved by ⁇ -secretase and released out of the cells was measured by western blot.
  • the APP precursor protein is cleaved first by ⁇ -secretase
  • sAPP ⁇ is released out of the cell.
  • the protein remaining attached to the membrane is cleaved again by ⁇ -secretase to produce ⁇ -amyloid.
  • the amount of ⁇ -secretase and sAPP ⁇ is proportional to the amount of the produced ⁇ -amyloid. Therefore, the amount of the two proteins was measured by western blot.
  • Compound 1 (butyrylphloroglucinol) reduced the amount of the sAPP ⁇ protein by about 20% at the concentration of 10 ⁇ g/mL and by about 70% at the concentration of 20 ⁇ g/mL as compared to the control group.
  • Compound 2 (2-propionyl-4-methylphloroglucinol) reduced the amount of sAPP ⁇ by about 40% at 20 ⁇ g/mL and by about 80% at 100 ⁇ g/mL as compared to the control group.
  • Compound 3 (2-butyryl-4-methylphloroglucinol) reduced the amount of sAPP ⁇ by about 40% at 10 ⁇ g/mL and by about 80% at 20 ⁇ g/mL as compared to the control group.
  • Compound 1 (butyryiphloroglucinol) reduced the amount of the ⁇ -secretase protein by about 10% at 10 ⁇ g/mL and by about 30% at 20 ⁇ g/mL.
  • Compound 2 (2-propionyl-4-methylphloroglucinol) reduced the amount of ⁇ -secretase by about 40% at 20 ⁇ g/mL and by about 60% at 100 ⁇ g/mL as compared to the control group.
  • Compound 3 (2-butyryl-4-methylphloroglucinol) reduced the amount of ⁇ -secretase by about 20% at 10 ⁇ g/mL and by about 30% at 20 ⁇ g/mL as compared to the control group.

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Abstract

The present disclosure relates to a use of a phloroglucinol-based compound and its salt for preventing and treating Alzheimer's disease. The pharmaceutical composition for preventing or treating Alzheimer's disease of the present disclosure fundamentally suppresses the cause of β-amyloid formation, thereby exerting a remarkable effect of allowing ultimate treatment of Alzheimer's disease. The present disclosure provides the use of the single substance, which has been isolated from Dryopteris crassirhizoma and identified, for preventing or treating Alzheimer's disease for the first time.

Description

CROSS REFERENCE TO RELATED APPLICATION(S)
This application is a U.S. National Stage Application of International Application No. PCT/KR2016/013351, filed on Nov. 18, 2016, which claims the benefit under 35 USC 119(a) and 365(b) of Korean Patent Application No. 10-2015-0161805, filed on Nov. 18, 2015, in the Korean Intellectual Property Office.
BACKGROUND 1. Field of the Invention
The present disclosure relates to a use of a phloroglucinol-based compound and its salt for preventing and treating Alzheimer's disease.
2. Description of Related Art
Dementia is a pathological condition which should be distinguished from normal aging. It is divided into Alzheimer's disease, vascular dementia and other dementias caused by alcoholism, trauma and sequela of Parkinson's disease according to the cause. Among them, Alzheimer's disease is known to be caused primarily by the toxicity of the neurotoxic protein β-amyloid.
According to the generally accepted hypothesis, neuronal cell death is induced by β-amyloid through the following process. First, β-amyloid is produced gradually from the amyloid precursor protein (APP) via the amyloidogenic pathway. The produced monomeric β-amyloid is aggregated with each other to form an oligomer. The aggregated form of β-amyloid induces neuronal cell death.
Accordingly, in order to suppress neuronal cell death caused by β-amyloid, it is necessary to suppress the production of the β-amyloid, suppress the aggregation of the monomeric β-amyloid to the oligomer or protect the cells from the toxicity of the β-amyloid.
Currently, acetylcholine precursors or drugs inhibiting the degradation of acetylcholine are administered as dementia medications in order to increase the concentration of acetylcholine in the brain. Representative drugs include tacrine, donepezil, rivastigmine, galantamine, etc.
Because the existing dementia medications mainly inhibit the acetylcholinesterase without preventing the formation or aggregation of β-amyloid, they cannot ultimately prevent or cure dementia. In addition, because the existing dementia medications are cholinergic drugs, they have the problems that they cannot be administered in combination with other cholinergic drugs, they may inhibit the effect of anticholinergic drugs, they may stimulate the vagus nerve by acting on the cardiovascular system and care should be taken when they are used in patients with a history of severe asthma or obstructive pulmonary disease.
Accordingly, it is the utmost importance to find a method allowing the ultimate treatment of Alzheimer's disease unlike the existing therapeutic agents, i.e., a drug that can suppress the production of β-amyloid while having low toxicity.
The inventors of the present disclosure have studied Dryopteris crassirhizoma for treatment and prevention of Alzheimer's disease. In doing so, they have found a use of an active ingredient capable of suppressing the production of β-amyloid from the ingredients of the herb, which has never been mentioned or studied regarding Alzheimer's disease, and have completed the present disclosure.
REFERENCES OF RELATED ART
Korean Patent Publication No. 10-2010-0082090.
Korean Patent Publication No. 10-2010-0012927.
SUMMARY OF THE INVENTION
The present disclosure is directed to providing a pharmaceutical composition for preventing or treating Alzheimer's disease.
The present disclosure is also directed to providing a method for preparing a pharmaceutical composition for preventing or treating Alzheimer's disease, which includes extracting and separating an active ingredient from Dryopteris crassirhizoma and formulating the same.
The present disclosure provides a pharmaceutical composition for preventing or treating Alzheimer's disease, which contains a phloroglucinol-based compound, an isomer thereof or a salt thereof.
The present disclosure also provides a method for preparing a pharmaceutical composition for preventing or treating Alzheimer's disease, which includes extracting and separating an active ingredient from Dryopteris crassirhizoma and formulating the same.
A pharmaceutical composition for preventing or treating Alzheimer's disease of the present disclosure fundamentally suppresses the cause of β-amyloid formation, thereby exerting a remarkable effect of allowing ultimate treatment of Alzheimer's disease.
The present disclosure provides a use of a single substance, which has been isolated from Dryopteris crassirhizoma and identified, for preventing or treating Alzheimer's disease for the first time.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an exemplary extraction process for obtaining a compound according to the present disclosure.
FIG. 2 shows an exemplary process of obtaining fractions for obtaining a compound according to the present disclosure.
FIG. 3 shows the 1H-NMR spectrum of Compound 1 identified as a single substance.
FIG. 4 shows the 13C-NMR spectrum of Compound 1 identified as a single substance.
FIG. 5 shows the structure of Compound 1.
FIG. 6 shows the 1H-NMR spectrum of Compound 2 identified as a single substance.
FIG. 7 shows the 13C-NMR spectrum of Compound 2 identified as a single substance.
FIG. 8 shows the structure of Compound 2.
FIG. 9 shows the 1H-NMR spectrum of Compound 3 according to the present disclosure.
FIG. 10 shows the 13C-NMR spectrum of Compound 3 according to the present disclosure.
FIG. 11 shows the structure of Compound 3 according to the present disclosure.
FIG. 12 shows a result of investigating the cytotoxicity of Compounds 1 and 2.
FIG. 13 shows a result of investigating the cytotoxicity of Compound 3.
FIG. 14 shows a result of investigating the inhibition of β-amyloid formation by Compounds 1-3 through western blot.
FIG. 15 shows a result of comparing the inhibition of β-amyloid formation by Compounds 1-3.
FIG. 16 shows a result of investigating the effect of Compound 1 on β-secretase through western blot.
FIG. 17 shows a result of investigating the effect of Compound 1 on β-secretase.
FIG. 18 shows a result of investigating the effect of Compound 2 on β-secretase through western blot.
FIG. 19 shows a result of investigating the effect of Compound 2 on β-secretase.
FIG. 20 shows a result of investigating the effect of Compound 3 on β-secretase through western blot.
FIG. 21 shows a result of investigating the effect of Compound 3 on β-secretase.
 DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present disclosure is described in more detail.
The present disclosure relates to a pharmaceutical composition for preventing or treating Alzheimer's disease, which contains a phloroglucinol-based compound, an isomer thereof or a salt thereof.
The phloroglucinol-based compound defined in the present disclosure has a basic structure of Chemical Formula 1:
Figure US11096906-20210824-C00001
In Chemical Formula 1, the positions 2 and 4 may be substituted with an alkyl or acyl group.
Specifically, the phloroglucinol-based compound of the present disclosure may be one or more selected from a group consisting of butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol and 2-butyryl-4-methylphloroglucinol.
In an exemplary embodiment of the present disclosure, butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol and 2-butyryl-4-methylphloroglucinol exert a remarkable effect of inhibiting β-amyloid formation without showing cytotoxicity at an effective concentration (see FIGS. 12-21).
In particular, Compound 3, which showed toxicity at a concentration of 100 μg/mL, reduced the amount of sAPPβ almost perfectly at 20 μg/mL where no toxicity was observed and also effectively decreased the amount of β-secretase in Test Example 1. Considering that an increased administration dose of an active ingredient, etc. generally leads to increased cytotoxicity and drug-related side effects, the remarkable effect at a low administration dose means a high value as a drug for treating Alzheimer's disease.
The pharmaceutical composition of the present disclosure may contain one or more active ingredient selected from a group consisting of butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol, 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof.
The pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains one of butyryiphloroglucinol, 2-propionyl-4-methylphloroglucinol, 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
Specifically, the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains butyryiphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
Also, the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains 2-propionyl-4-methylphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
In addition, the pharmaceutical composition of the present disclosure may exert an effect of preventing or treating Alzheimer's disease even when it contains 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof as a single active ingredient.
The salt contained in the pharmaceutical composition of the present disclosure may be a physiologically acceptable salt of an inorganic acid, an organic acid, an inorganic base or an organic base.
For example, the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid or phosphoric acid, the organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc., although not being limited thereto.
The term Alzheimer's disease used in the present disclosure refers to dementia caused by Alzheimer's disease, i.e., dementia caused by formation and buildup of β-amyloid in the brain tissue. Any dementia caused by formation and buildup of β-amyloid is included in the scope of the present disclosure.
The pharmaceutical composition for preventing or treating Alzheimer's disease containing the phloroglucinol-based compound according to the present disclosure may be applied to an animal including human.
The phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure may be prepared through chemical synthesis or may be obtained by extracting from Dryopteris crassirhizoma.
In an exemplary embodiment of the present disclosure, the phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure is isolated from Dryopteris crassirhizoma. Dryopteris crassirhizoma is a perennial grass belonging to the family Dryopteridaceae (Aspidiaceae).
When the phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure is obtained by extraction, it may be obtained by cold extraction, hot extraction, thermal extraction, ultrasonic extraction, etc. using a commonly used extractor, ultrasonic extractor or fractionator.
The phloroglucinol-based compound contained in the pharmaceutical composition of the present disclosure may be isolated by extracting with one or more solvent selected from a group consisting of propanol, isopropanol and methanol. Specifically, one or more solvent selected from a group consisting of isopropanol or butanol may be used.
Specifically, the solvent used in the extraction may be diluted to 50-99% (v/v) with water.
After extracting Dryopteris crassirhizoma with one or more solvent selected from a group consisting of propanol, isopropanol and methanol, removing the remnant of Dryopteris crassirhizoma and filtering with filter paper, the filtrate may be concentrated using a vacuum rotary evaporator or a vacuum drier and then stored at room temperature.
The extract may be further fractionated simultaneously or sequentially using one or more solvent selected from a group consisting of hexane, methylene chloride, ethyl acetate, butanol and water. The fractionation solvent may be specifically butanol, more specifically 30-99% (v/v) butanol diluted with water.
The fraction may be concentrated using a vacuum rotary evaporator or a vacuum drier and then stored at room temperature.
The fraction obtained by fractionating simultaneously or sequentially using one or more solvent selected from a group consisting of hexane, methylene chloride, ethyl acetate, butanol and water may be separated by ion-exchange chromatography, silica gel chromatography or medium pressure liquid chromatography (MPLC).
As a solvent used in the chromatography, specifically methanol, acetonitrile or methyl chloride may be used, although not being limited thereto.
The phloroglucinol-based compound according to the present disclosure provides a remarkable use in preventing or treating Alzheimer's disease.
In an exemplary embodiment of the present disclosure, the phloroglucinol-based compound can fundamentally suppress the formation of β-amyloid by reducing sAPPβ in a concentration-dependent manner (see FIGS. 14 and 15).
Also, in an exemplary embodiment of the present disclosure, the phloroglucinol-based compound can fundamentally suppress the formation of β-amyloid by inhibiting β-secretase in a concentration-dependent manner (see FIGS. 16-21).
That is to say, the pharmaceutical composition containing the phloroglucinol-based compound of the present disclosure, an isomer thereof or a salt thereof can suppress the formation of β-amyloid, which is the fundamental problem of Alzheimer's disease, unlike the currently commercially available drugs that simply suppress the progress of Alzheimer's disease through metabolism of acetylcholine, such as tacrine, donepezil, rivastigmine, galantamine, etc. Accordingly, the pharmaceutical composition of the present disclosure can be used directly for preventing and treating Alzheimer's disease.
The administration dose of the pharmaceutical composition according to the present disclosure may be determined by considering administration method, the age, sex and condition of a patient, the severity of a disease, the absorption rate of the active ingredient in vivo, the rate of inactivation and the drug administered in combination. The daily dosage of the active ingredient may be 0.1-500 mg/kg (body weight), specifically 0.1-400 mg/kg (body weight), more specifically 1-300 mg/kg (body weight) and the administration may be made once or several times a day, although not being limited thereto.
The pharmaceutical composition according to the present disclosure may be formulated by containing an inert carrier, a diluent or both of them.
Examples of the inert carrier or diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, corn starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, citric acid, tartaric acid, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, physiological saline, etc., although not being limited thereto.
The pharmaceutical composition of the present disclosure may further contain a commonly used filler, extender, binder, disintegrant, anti-agglomerant, lubricant, wetting agent, pH control agent, nutrient, vitamin, electrolyte, alginic acid or its salt, pectic acid or its salt, protective colloid, glycerin, fragrance, emulsifier, antiseptic, etc. Other suitable lubricants and excipients that may be used are described in the following literatures: Handbook of Pharmaceutical Excipients, 7th edition, American Pharmaceutical Association; The Theory and Practice of Industrial Pharmacy, 3rd edition, Lachman, Leon, 1976; Pharmaceutical Dosage Forms: Tablets Volume 1, 3rd edition, Lieberman, Hebert A., et al., 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's Pharmaceutical Sciences, 15th edition, 1975.
The pharmaceutical composition according to the present disclosure may be prepared into an oral or parenteral formulation by containing an additive including the above-described carrier or diluent.
Formulations for oral administration include a tablet, a capsule, a pill, a powder, a granule, a suspension, a syrup, etc. Formulations for parenteral administration include a cream, a lotion, an ointment, a liquid, a gel, a cataplasma, a patch, an aerosol, a fluid extract, an elixir, an infusion, a sachet, an injection, etc.
The content of the phloroglucinol-based compound in the pharmaceutical composition for preventing or treating Alzheimer's disease may be 0.001-99.9 wt %, 0.1-99 wt % or 1-50 wt %. However, the content may be controlled adequately without being limited thereto.
The pharmaceutical composition for preventing or treating Alzheimer's disease of the present disclosure may further contain a substance known to be effective in treating dementia in addition to the active ingredient. Examples may include tacrine, donepezil, rivastigmine, galantamine, etc., although not being limited thereto.
Hereinafter, the present disclosure will be described in detail through examples. However, the following examples are for illustrative purposes only and it will be apparent to those of ordinary skill in the art that the scope of the present disclosure is not limited by the examples.
Example 1: Preparation of Dryopteris crassirhizoma Extract or Fractions
1. Preparation of Methanol or Isopropanol Extract of Dryopteris Crassirhizoma
After adding 90% methanol to 6 kg of Dryopteris crassirhizoma with impurities removed and keeping at room temperature for 24 hours, a filtrate obtained by filtering through filter paper was concentrated using a vacuum rotary evaporator (EYELA). 325 g of an extract in the form of a brown crystalline powder was obtained by repeating this process 3 times. Also, after adding 90% isopropanol to 6 kg of Dryopteris crassirhizoma with impurities removed, 390 g of an extract in the form of a brown crystalline powder was obtained through the same procedure.
2. Preparation of Fractions of Dryopteris crassirhizoma
The concentrated methanol or isopropanol extract of Dryopteris crassirhizoma was fractionated with two immiscible solvents based on the difference in polarity. Hexane, methylene chloride, ethyl acetate, butanol and water layers were fractionated and concentrated sequentially. This process was repeated 3 times. The concentrates were stored at 4° C. until use. 16 g of a hexane layer, 3 g of a methylene chloride layer, 54 g of an ethyl acetate layer, 80 g of a butanol layer and 140 g of a water layer were obtained.
Example 2: Separation and Purification of Compounds 1-3
The fractionated butanol layer extract (80 g) was subjected to MCI column chromatography. 30-100% methanol was used as a mobile phase and a total of 6 fractions were obtained (S1-S6). Based on TLC and HPLC results, the fifth fraction (S5, 3.5 g) was separated by MPLC. The mobile phase started from methylene chloride (MC):MeOH:water (10:1:1) to MC:MeOH:water=10:2:1, 10:3:1, 10:4:1, 10:5:1. As a result, a total of 15 fractions were obtained and they were combined into 10 fractions through TLC and HPLC. Compound 1 (10 mg), Compound 2 (5.5 mg) and Compound 3 (15 mg) were obtained as pure single substances from the 1st fraction (255 mg) through HPLC (solvent: 40-50% ACN).
Example 3: Structural Identification of Compound 1
Compound 1 was separated as a scarlet powder. Two proton peaks at δH 5.81 (2H, s, H-4, H-6) in the 1H NMR spectrum were identified as aromatic protons at 1, 3 and 5 positions by 13C NMR. A butyryl group was inferred from the correlation between two methylene protons at 2.97 (2H, t, J=7.4 Hz, H-2′) and 1.60 (2H, m, H-3′) and a methyl proton 0.92 (3H, t, J=7.4 Hz, Me-4′). δC 205.55 (C-1′), 164.90 (C-5), 164.66 (C-1, 3), 104.26 (C-2), 95.10 (C-4, 6), 45.48 (C-2′), 18.19 (C-3′) and 14.33 (C-4′) were identified from 13C NMR. The backbone of phloroglucinol was identified based on the NMR result. After comparing with the reference, Compound 1 was identified as butyryiphloroglucinol.
Example 4: Structural Identification of Compound 2
Compound 2 was separated as a scarlet powder. One proton peak at δH 5.92 (s, H-6) in the 1H NMR spectrum was identified as aromatic protons at 1, 3 and positions by 13C NMR. A propionyl group was inferred from the correlation between a methylene proton 3.09 (2H, q, H-2′) and a methyl proton (3H, t, J=7.4 Hz, Me-3′) and one methyl proton 1.94 (3H, s, Me-1″) was identified. δC 208.70 (C-1′), 163.46 (C-5), 162.30 (C-3), 159.99 (C-1), 103.65 (C-4), 102.09 (C-2), 93.33 (C-6), 36.61 (C-2′), 7.93 (C-3′) and 5.91 (C-1″) were identified from 13C NMR. The backbone of phloroglucinol was identified based on the NMR result. After comparing with the reference, Compound 2 was identified as 2-propionyl-4-methylphloroglucinol.
Example 5: Structural Identification of Compound 3
Compound 3 was separated as a scarlet powder.
One proton peak at δH 6.01 (s, H-6) in the 1H NMR spectrum was identified as aromatic protons at 1, 3 and 5 positions by 13C NMR. A butyryl group was inferred from the correlation between a methylene proton 2.97 (2H, t, J=7.4 Hz, H-2′), another methylene proton 1.60 (2H, m, H-3′) and a methyl proton 0.92 (3H, t, J=7.4 Hz, Me-4′) and one methyl proton 1.84 (3H, s, Me-1″) was identified. δC 206.52 (C-1′), 163.68 (C-5), 163.03 (C-3), 161.24 (C-1), 103.23 (C-4), 102.69 (C-2), 95.74 (C-6), 41.97 (C-2′), 19.44 (C-3′), 13.57 (C-4′) and 7.84 (C-1″) were identified from 13C NMR. The backbone of phloroglucinol was identified based on the NMR result.
After comparing with the reference, Compound 3 was identified as 2-butyryl-4-methylphloroglucinol.
Test Example 1: Investigation of Toxicity of Identified Compounds
The cytotoxicity of Compounds 1-3 separated and identified in Examples 1-5 was investigated by MTT-based cytotoxicity assay. APP*t-CHO cells treated with Compounds 1-3 were cultured for 24 hours. After adding a 5 mg/mL MTT solution, the cells were cultured for 4 hours. After removing the culture medium and lysing the cells for 30 minutes by adding DMSO, absorbance was measured at 540 nm using the Emax precision microplate reader (Molecular Devices, CA, USA). Compounds 1 and 2 showed no toxicity even at the concentration of 100 μg/mL, whereas Compound 3 showed toxicity at the concentration of 30 μg/mL or higher (see FIGS. 12 and 13).
Test Example 2: Suppression of β-Amyloid Formation by Phloroglucinol-Based Compounds
In order to evaluate the ability of suppressing β-amyloid formation of Compounds 1-3, APPwt-CHO cells obtained by overexpressing APP in CHO cells were used and the amount of the sAPPβ protein cleaved by β-secretase and released out of the cells was measured by western blot. When the APP precursor protein is cleaved first by β-secretase, sAPPβ is released out of the cell. The protein remaining attached to the membrane is cleaved again by γ-secretase to produce β-amyloid. Accordingly, the amount of β-secretase and sAPPβ is proportional to the amount of the produced β-amyloid. Therefore, the amount of the two proteins was measured by western blot.
As a result, Compound 1 (butyrylphloroglucinol) reduced the amount of the sAPPβ protein by about 20% at the concentration of 10 μg/mL and by about 70% at the concentration of 20 μg/mL as compared to the control group. Compound 2 (2-propionyl-4-methylphloroglucinol) reduced the amount of sAPPβ by about 40% at 20 μg/mL and by about 80% at 100 μg/mL as compared to the control group. Compound 3 (2-butyryl-4-methylphloroglucinol) reduced the amount of sAPPβ by about 40% at 10 μg/mL and by about 80% at 20 μg/mL as compared to the control group. Also, Compound 1 (butyryiphloroglucinol) reduced the amount of the β-secretase protein by about 10% at 10 μg/mL and by about 30% at 20 μg/mL. Compound 2 (2-propionyl-4-methylphloroglucinol) reduced the amount of β-secretase by about 40% at 20 μg/mL and by about 60% at 100 μg/mL as compared to the control group. Compound 3 (2-butyryl-4-methylphloroglucinol) reduced the amount of β-secretase by about 20% at 10 μg/mL and by about 30% at 20 μg/mL as compared to the control group. To conclude, all of Compounds 1-3 showed the ability of suppressing the formation of the β-amyloid protein (FIGS. 14-21).

Claims (18)

What is claimed is:
1. A pharmaceutical composition for treating Alzheimer's disease, comprising one or more phloroglucinol-based compound selected from the group consisting of butyrylphloroglucinol, 2-propionyl-4-methylphloroglucinol and 2-butyryl-4-methylphloroglucinol, an isomer thereof or a salt thereof,
wherein the pharmaceutical composition further comprises a substance effective in treating dementia.
2. The pharmaceutical composition for preventing or treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises butyrylphloroglucinol as an active ingredient.
3. The pharmaceutical composition for preventing or treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises butyrylphloroglucinol as a single active ingredient.
4. The pharmaceutical composition for preventing or treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises 2-propionyl-4-methylphloroglucinol as an active ingredient.
5. The pharmaceutical composition for preventing or treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises 2-propionyl-4-methylphloroglucinol as a single active ingredient.
6. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises 2-butyryl-4-methylphloroglucinol as an active ingredient.
7. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises 2-butyryl-4-methylphloroglucinol as a single active ingredient.
8. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the salt is a physiologically acceptable salt of an inorganic acid, an organic acid, an inorganic base or an organic base.
9. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the phloroglucinol-based compound is isolated from Dryopteris crassirhizoma.
10. The pharmaceutical composition for treating Alzheimer's disease according to claim 9, wherein the phloroglucinol-based compound is isolated by extracting Dryopteris crassirhizoma with one or more solvent selected from the group consisting of propanol, isopropanol and methanol.
11. The pharmaceutical composition for treating Alzheimer's disease according to claim 10, wherein the solvent extract is fractionated simultaneously or sequentially with one or more solvent selected from the group consisting of hexane, methylene chloride, ethyl acetate, butanol and water.
12. The pharmaceutical composition for treating Alzheimer's disease according to claim 11, wherein the fraction is separated into a single substance by being subjected to ion-exchange chromatography and then to silica gel chromatography or medium pressure liquid chromatography (MPLC).
13. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition comprises one or more selected from the group consisting of an inert carrier and a diluent.
14. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the pharmaceutical composition is prepared into an oral or parenteral formulation.
15. The pharmaceutical composition for treating Alzheimer's disease according to claim 14, wherein the pharmaceutical composition is prepared into the oral or parental formulation selected from the group consisting of a tablet, a capsule, a pill, a powder, a granule, a suspension, a syrup, a cream, a lotion, an ointment, a liquid, a gel, a cataplasma, a patch, an aerosol, a fluid extract, an elixir, an infusion, a sachet and an injection.
16. The pharmaceutical composition for treating Alzheimer's disease according to claim 1, wherein the substance is selected from the group consisting of tacrine, donepezil, rivastigmine and galantamine.
17. The pharmaceutical composition for preventing or treating Alzheimer's disease according to claim 1, wherein a concentration of butyrylphloroglucinol is 10 μg/mL to 20 μg/mL, a concentration of 2-propionyl-4-methylphloroglucinol is 20 μg/mL to 100 μg/mL, and a concentration of 2-butyryl-4-methylphloroglucinol is 10 μg/mL to 20 μg/mL.
18. A method of treating Alzheimer's disease comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 1 to a subject suffering the Alzheimer's disease.
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